Twenty years ago stroke doctors celebrated the arrival of a powerful new weapon: the clot-clearing drug tPA. It was hailed as a lifesaver and has proved to be one for hundreds of thousands of patients since. TPA was the first and is still the only medicine approved by the U.S. Food and Drug Administration for treating strokes caused by clots that block blood flow to the brain. But like so many medical marvels, tPA (which stands for tissue plasminogen activator) has turned out to have serious limitations. It needs to be administered within three hours of symptom onset, does not last long in the body before it loses effectiveness, can cause uncontrolled bleeding and often fails to break up large clots.

For many of the nearly 800,000 Americans who every year suffer ischemic strokes, as the brain blockages are called, these shortcomings can be deadly. Nearly 130,000 die. Sadly, there have been no good alternatives to tPA since it debuted.

Recently doctors and scientists have broken this long-standing clinical stalemate with new tools to put a dent in those grim numbers. One innovation, a tiny wire device called a stent retriever, can be snaked up into the blood vessels leading to the brain to pull out large clots. “It's the first proven, effective treatment for acute stroke in a generation,” says Jeffrey Saver, director of the Stroke Center at the University of California, Los Angeles. Approved by the FDA in 2012, the stent retriever got a boost this year when the journal Stroke reported data showing many more patients treated with a retriever resumed normal life than did patients who received tPA. (The retriever manufacturer, Medtronic, provided support for the studies. Neurologist Bruce Campbell of the Royal Melbourne Hospital in Australia, who co-led the analysis, notes that Stroke has “strict independent-peer-review processes” to guard against bias.) Researchers are also developing better clot-detection scans, as well as a technique involving magnetism that guides tPA directly to the problem. This method could help eliminate dangerous obstructions elsewhere in the body, as well as in the brain.

Big Clots, Big Trouble

Of all of tPA's drawbacks, the most troublesome is its inadequacy against big clots, which can block large blood vessels at the base of the brain; they cause about 25 to 30 percent of all strokes. Although it works well against smaller clots in narrower vessels, a safe dose of the drug—which is delivered intravenously—often does not last long enough in the bloodstream to dissolve the big clots, and increasing the dose raises the risk of bleeding. “All you need to see is one intracranial bleed from tPA, and you realize you've got to pause before you give that medication,” says Thomas Maldonado, a clot specialist at New York University's Langone Medical Center.

This is where the stent retriever has an advantage. It is a narrow tube that can be threaded up from the femoral artery in the leg to the site of the clot. Then wire mesh on the end of the retriever, which expands like an accordion, is pushed into the clot. The mesh tendrils keep the clot from breaking apart in the brain—which could be deadly—and help separate it from blood vessel walls. The device is next pulled out of the body, and the clot comes with it. (In years past, doctors had tried a device with a corkscrew tip but found it was not as good at clearing the clot.)

Another advantage the device has over the drug is that the time window for the use of the stent retriever after symptoms arise is double that of tPA—six hours instead of three. The Stroke analysis found that blood flow in a vessel blocked by a large clot was successfully restored in 236 of 306 patients, or 77 percent, treated with the stent retriever. With tPA alone, the success rate was around 37 percent.

Like all surgical interventions, the stent retriever carries the risk of complications. The main one is bleeding, which is why patients with high blood pressure and the strained vessels that go with it may not be candidates for the procedure. “There's also a chance of the guide wire or some other manipulation of the device poking through the blood vessel during the procedure,” Saver says.

A much less common complication, Saver adds, is a piece of the clot breaking off as it is being pulled out, escaping into a new artery and causing a new stroke in a different area than the initial one. It happens in about 2 to 3 percent of cases, he says.

Help from Imaging

The damage that blood clots do is not limited to strokes. Every year as many as 900,000 people in the U.S. develop blood clots in their legs, called deep vein thrombosis (DVT). Aside from the localized discomfort and pain it causes, DVT can travel to the lungs and become potentially lethal pulmonary embolisms, which kill an estimated 100,000 people annually. These two types of clots are usually treated with the anticoagulants heparin (for acute situations) and warfarin (for long-term problems), and surgery may be used in serious cases. The FDA approved tPA for the acute treatment of lung clots in 2002; although it carries the usual risks and complications, it can reduce the size of clots, which the anticoagulants cannot do. The drug is also gaining traction as a treatment for some cases of leg blockages.

Knowing more precisely where these clots are would help doctors go after them: location can affect choice of drugs or other treatments. Alas, current imaging methods have limitations. Existing technologies are “very good if we know where we're looking,” says Peter Caravan, a radiologist and co-director of the Institute for Innovation in Imaging at Massachusetts General Hospital, but there is currently no single whole-body test that can spot blood clots anywhere that they might form. Ultrasound is the first choice for finding a clot in the legs, and computed tomography (CT) scans readily detect pulmonary embolisms. CT is also the primary imaging choice for patients who arrive at the hospital with symptoms of stroke. “But if we don't know where to look, we have to subject the patient to a battery of tests,” Caravan says, a costly and time-consuming process that can delay critical treatment.

To address the problem, Caravan and his team have invented an imaging agent that, when injected into the bloodstream, binds to fibrin, the meshlike protein that forms clots, and makes it visible to a scanner. It has potential applications for all clots, including those that cause strokes. “About a third of ischemic strokes are of unknown origin,” Caravan says. “You may think, at first, ‘So what? You had the stroke—why do you care where it came from?’ But it's really about preventing that second stroke. Your biggest risk of having a stroke is if you've already had one.”

Because the experimental probe binds to fibrin (and “lights up” in a positron-emission tomography scan), it can help establish how dangerous a clot is: younger clots, which have more fibrin than older ones, are less stable and more likely to travel to the lungs. They can also make it up to the brain, triggering a stroke. Further, tPA is more effective against fibrin-rich young clots than it is against older clots, and so the probe could help determine which clots to attack with the drug. After a series of animal experiments, researchers began safety testing of the new agent in healthy human subjects this past spring.

Some doctors think that tPA could work faster and prevent strokes more successfully if the drug could be guided swiftly and efficiently to the clot rather than simply being injected into the bloodstream. Researchers at Houston Methodist Hospital are experimenting with a way to transport tPA to the clot while protecting it from the body's defenses, which degrade the drug. They are experimenting with iron oxide nanoparticles, stuffed with tPA and “biochemically camouflaged” with a coating of the naturally occurring blood protein albumin. The albumin jacket fools the body's defenses and gives the tPA extra time to work on the clot; the iron oxide enables monitoring with magnetic resonance imaging, remote guidance of the nanoparticles with external magnetic fields and magnetic heating at the site to accelerate clot dissolution. And because the tPA does not degrade while it is being ferried to the clot inside the iron oxide, the dose can be smaller, reducing the risk of hemorrhage. Results with human tissue cultures and animal models have been promising, and clinical trials in humans are planned.

Of course, stopping blood clots from forming in the first place would be even better. There is a growing list of clotting conditions caused by genetic mutations, and researchers around the country, including a team at N.Y.U. Langone, are analyzing the role that genes play in clots. “That's the genetic handprint we're looking for,” Maldonado says. The goal is to develop a genetic test that would show if a person is at increased risk and to offer preventive treatment such as an anticoagulant. This approach could hinder the blockages, making elaborate feats with wires and magnets unnecessary.